1. Technical Field
The present invention relates to covalent modification of abnormal prions for protecting against transmission of prion disease.
2. Related Art
Prions are proteins that occur in the brains of all mammals studied to date. Although the normal function of a prion protein (xe2x80x9cprionxe2x80x9d) is not well understood, recent research on mice lacking the prion protein gene (which encodes the prion protein) suggests that the prion protein protects the brain against dementia and other degenerative problems associated with old age. Such a prion is a xe2x80x9cnormal prion.xe2x80x9d
The normal prion protein (PrP) is a glycoprotein constitutively expressed on the neuronal cell surfaces of mammals. The normal prion protein can be altered, however, as a consequence of genetic mutations or induced changes in protein shape and structure (conformational changes). Indeed, such altered or xe2x80x9cabnormalxe2x80x9d prion proteins (also called defective prions, infective prions, distorted prions, etc.) are implicated in the pathogenesis of a number of inheritable and infectious spongiform encephalopathies in human and nonhuman animals (see FIG. 6 for both genetic and non-genetic modes of transmission). As infectious disease agents, the abnormal protein is transferred from one animal to another via multiple routes. In humans, Creutzfeldt-Jakob Disease (CJD) has been transmitted via blood transfusion (Iatrognic transmission) and a bovine derived disease (CJD-New Variant) has been though to be transmitted via the consumption of meat obtained from cattle infected with Bovine Spongiform Encephalopathy (BSE). Although some abnormal prions may be transmitted genetically, non-genetic modes of transmission are possible.
The concept of a protein as an infectious disease agent was first proposed by Prusiner in the early 1980""s (Prusiner, 1982). Since the initial proposal of infectious proteins was made, the molecular/genetic basis of the some human prion diseases have been characterized as shown in FIG. 6. In addition, animals models of prion diseases have also been successfully developed.
Noteworthy aspects of diseases listed in FIG. 12 are as follows. CJD occurs when codon 129 is homozygous for valine or heterozygous for methionine and valine. Fatal Familial Insomnia (FFI) occurs when codon is 129 is homozygous for methionine. Codon 102, in relation to Gerstmann-Straussler Syndrome (GSS), produces a prion protein that accumulates in the endoplasmic reticulum. Kuru, found in the Fore tribe of New Guinea, is spread by ritual cannibalism in which mourners eat the brains of their dead relatives, a practice that has since ceased. For the non-human diseases of Scrapie, BSE, Transmissible Mink Encephalopathy (TME), and Chronic Wasting Disease (CWD) of Deer, a clear genetic predisposition is present but may not be sufficient; and some evidence suggests that an environmental agent is necessary to induce at least some genetic versions of the disease. BSE is believed to have resulted from feeding healthy cattle a processed form of sheep, wherein the sheep had died from the related disease of Scrapie.
Abnormal prions transform, via conformational changes, any normal prions they encounter into copies of themselves, as illustrated in FIG. 1. In FIG. 1, an abnormal prion 12 in a receptive host animal interacts with a normal prion 10 in the animal, resulting in a prion transformation process 14 which results in conversion of the normal prion 10 into an abnormal prion 16. The abnormal prion 12 acts as a template for the aforementioned transformation of the normal prion 10 such that the normal prion 10, when transformed to the abnormal prion 16, assumes the conformational shape of the introduced abnormal prion 12. The representation of the normal prion 10 and abnormal prion 12 in FIG. 1 is a symbolic representation of a normal prion and an abnormal prion, respectively, and does not depict or suggest the geometry of normal and abnormal prions. A normal prion includes strands of a helical shape that is called an xe2x80x9calpha helixxe2x80x9d and such strands appear twisted into a spiral. An abnormal prion includes both helical strands and strands arranged in a planar shape called a xe2x80x9cbeta-sheet.xe2x80x9d The transformation process 14 of FIG. 1 converts the alpha-helix structure of the normal prion 10 into the beta-sheet structure of the abnormal prion 12.
Assuming that the transformation process 14 of FIG. 1 occurs in the brain of a host animal, the transformation process 14 continues like a chain reaction and eventually generates enough abnormal prions to cause destruction of brain neurons, resulting in an inflammatory condition in the brain that is sponge-like in appearance. Hence, abnormal prions cause brain destruction. Unfortunately, there are no known cures for prion diseases.
Since prion disease, for which there is no known cure, can be transmitted between humans, between non-human animals, and from non-human animals to humans, there are high health and economic costs relating to prion disease. Accordingly, there is a need for protecting against transmission of prion disease.
The present invention provides a method for forming a prion-physiological structure, comprising:
providing an abnormal prion that has a transforming power over a normal prion; and
covalently bonding a linker molecule to the abnormal prion, wherein a polymer is covalently attached to the linker molecule to form a polymerized abnormal prion that does not have the transforming power over the normal prion.
The present invention provides a prion-physiological structure, comprising:
an abnormal prion that has a transforming power over a normal prion; and
a linker molecule covalently bonded to the abnormal prion, wherein a polymer is covalently attached to the linker molecule to form a polymerized abnormal prion that does not have the transforming power over the normal prion.
The present invention provides a prion-physiological structure, comprising:
an abnormal prion that has a transforming power over a normal prion; and
means for covalently bonding a linker molecule to the abnormal prion, wherein a polymer is covalently attached to the linker molecule to form a polymerized abnormal prion, and wherein the polymer has a long chain length that inactivates the transforming power.
The present invention protects against transmission of prion disease.